Studies over the past 15 years suggest that the prevailing rate of epilepsy in the United States is between 5 and 20 per 1000, and recent estimates drawn from population surveys indicate that the higher rates are closer to the true prevalence. This means that 1 to 4 million Americans suffer from some form of epilepsy. For certain types of seizures there are no specific drugs available; for seizures that are controlled with currently available therapy, a new drug may allow a reduction in the toxic side effects. Despite these facts, between 1960 and 1974, no new anticonvulsant drug was marketed in the United States (with the exception of diazepam, which was marketed primarily as a minor tranquilizer) (Vida, J. A. "Anticonvulsants," Academic Press, New York, 1977). However, since the approval of carbamazepine in 1974 and clonazepam in 1975, and sodium dipropylacetate, eterobarb, mexiletine and others in 1977-1978, there has been a resurgence of interest in the development of better anticonvulsant drugs for the management of epilepsy. Also responsible for this renewed interest is the establishment of the Anticonvulsant Screening Project of the Antiepileptic Drug Development (ADD) Program of NINCDS (National Institute of Neurological and Communicative Disorders and Stroke) of NIH, in January, 1975.
In recent years hundreds of different heterocyclic compounds have been synthesized and screened for anticonvulsant activity. These include mostly five and six membered ring systems containing up to three or four heteroatoms and seven membered ring systems related to the diazepines. Among the nitrogen containing heterocycles, a considerable amount of work has been done in the areas of five membered rings bearing one or two nitrogen atoms.
Five membered rings with 3 or 4 nitrogen atoms that have been investigated, include mostly, 1,2,4-triazoles and some tetrazoles. Very little has been done on 1H-1,2,3-triazoles (Popp, F. D., In "Anticonvulsants," J. A. Vida, Ed. Academic Press, New York, 1977).
The literature indicates that to date there are only two references relating to studies on the anticonvulsant potential of 1H-1,2,3-triazoles. Unlike the simple 1-5-substituted-1,2,3-triazoles of this invention, both these references are to fused ring benzotriazoles of the structures I and II shown below by Gilbert and Rumanowski (Gilbert, E. E., ##STR2## and Rumanowski, E. J., U.S. Pat. No. 3,592,822, 1971) and structure III by Wolf (Wolf, M., U.S. Pat. No. 3,394,143, 1968). In addition certain substituted 1H-1,2,3-triazoles IV and V have been shown to afford some degree of protection against oxotremorin induced tremors in mice at 100 mg/kg. (Miller, A. D., ##STR3## I CI, United States, Ger. Pat. No. 2,648,826 (Cl. C07D249/04), 05 May, 1977; U.S. application No. 626,140, 26th Oct., 1975, 53 pages) and (ICI Americas, Inc., Belg. 853,978 (Cl. C07D), 26th Oct. 1977, Appl. 26th Apr. 1977, 11 pages). Compounds of the type IV and V have been investigated as potential tranquilizers or antianxiety agents but not as anticonvulsants.
The 1,2,3-triazoles are a novel group of anticonvulsant compounds because their heterocyclic ring system is different from that of conventional anticonvulsant drugs. The presently marketed antiepileptic drugs, for the major part, have a dicarboximide function and/or a disubstituted quaternary carbon group (barbiturates, hydantoins, succinimides, oxazolidinediones) or closely related structure (pyrimidone). On the other hand, the dicarboximide function, which contributes to the inherent hypnotic and sedative activity of the barbiturates and related compounds, is absent in the triazoles.
The chemistry of 1,2,3-triazoles has been extensively studied (Gilchrist, T. L., and Gymer, G. E., "Advances in Heterocyclic Chemistry" Vol. 16, 1974, pp. 33-85; Benson, F. R., and Savell, W. L., Chemical Reviews, 46, 1, 1950; Boyer, J. H., in "Heterocyclic Compounds", Edited by R. C. Elderfield, Vol. 1, p. 384-461, Wiley, New York, 1961), which also include the applicant's own publications on the synthesis of 1-aryl-5-heteroaryl-substituted 1H-1,2,3-triazoles. However, with the exception of the few 1,2,3-triazoles mentioned earlier, no studies have been conducted on 1,2,3-triazoles for use as anticonvulsants.
As indicated, the present applicant has published two papers involving her work on triazoles. The publications discuss primarily a convenient general synthetic route for the preparation of 1,5-substituted 1,2,3-triazoles by permanganate oxidation of the respective triazolines. (Kadaba, P. K. "Synthesis, International Journal of Methods in Synthetic Organic Chemistry," No. 9: September, 1978, pp. 694-695). (Kadaba, P. K., "Journal fur praktische Chemie," Vol. 324, 1982, pp. 857-864.)
In both these publications, however, there is no disclosure of the use of any of the 1,2,3-triazole compounds as anticonvulsants.